Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-24349-5
Keywords
-
Categories
Funding
- HPCI system [hp170254, hp180201, hp180274, hp190097, hp190181, hp200129, hp200135]
- MEXT [19H05645]
- National Science Foundation [MCB 1817307]
- National Institutes of Health [R35 GM126948]
- MEXT
- Program for Promoting Researches on the Supercomputer Fugaku (Biomolecular dynamics in a living cell/MD-driven Precision Medicine)
- RIKEN
Ask authors/readers for more resources
The cell is crowded with proteins and other biomolecules, and the binding dynamics of an inhibitor with c-Src kinase can change in crowded environments compared to dilute solutions, potentially due to local conformational shifts in c-Src kinase. The presence of crowders like bovine serum albumins can reduce the efficacy of the inhibitor in experimental assays, highlighting the importance of understanding ligand binding pathways in crowded cellular environments.
The inside of a cell is highly crowded with proteins and other biomolecules. How proteins express their specific functions together with many off-target proteins in crowded cellular environments is largely unknown. Here, we investigate an inhibitor binding with c-Src kinase using atomistic molecular dynamics (MD) simulations in dilute as well as crowded protein solution. The populations of the inhibitor, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1), in bulk solution and on the surface of c-Src kinase are reduced as the concentration of crowder bovine serum albumins (BSAs) increases. This observation is consistent with the reduced PP1 inhibitor efficacy in experimental c-Src kinase assays in addition with BSAs. The crowded environment changes the major binding pathway of PP1 toward c-Src kinase compared to that in dilute solution. This change is explained based on the population shift mechanism of local conformations near the inhibitor binding site in c-Src kinase. The intracellular compartment is a crowded environment. Here, the authors use molecular dynamics (MD) simulations to assess inhibitor binding to c-Src kinase and show how ligand binding pathways differ in crowded and dilute protein solutions, highlighting the role of c-Src Tyr82 sidechain.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available